1. Field of the Invention
The present invention relates to compositions and methods for enhancing contrast in imaging internal structures and functions of living subjects.
2. Imaging Modalities
Imaging of internal structures and functions of living subjects may be accomplished by applying electromagnetic radiation from external sources (as in conventional x-rays and computerized axial tomography) or internal sources (as in PET or positron emission tomography and radionuclide scans). Use of ionizing radiation is avoided in imaging with nuclear magnetic resonance (NMR) and untrasonography, making these methods advantageous for many applications.
Whatever the imaging modality, consideration is given to means of increasing image contrast through localization of contrast agents in the region to be imaged. Such agents are frequently metals which emit, absorb, or scatter energy or, as in the case with NMR agents, increase the image signal strength locally. For best effect, agents must be localized. This may be accomplished, for example, by direct injection of contrast agent (as in myelograms or retrograde urethrograms), through metabolic uptake of an agent (as in PET), and by conjugation of contrast agents with monoclonal antibodies which tend to accumulate in certain tissues. The latter process in particular has been used in NMR image enhancement with chelated metal ions. Though well known, the process has several shortcomings:
1 preparation of the antibody is complex; PA1 2 diminished immunoreactivity of the antibody occurs following conjugation; PA1 3 there is limited uptake of the conjugate by the target tissue; and PA1 4 there may be unfavorable interactions between the chelated ion and the antibody. PA1 y is 3 or 4; PA1 R is (CH.sub.2).sub.z P(.dbd.0)OR.sup.1 OR.sup.2 ; PA1 R.sup.1 is H or CH.sub.3; PA1 R.sup.2 is butyl, pentyl or hexyl; and PA1 z is 1 to 3. PA1 y is 3 or4; PA1 R is (CH.sub.2).sub.z P(.dbd.O)OR.sup.1 OR.sup.2 ; PA1 R.sup.1 is H or CH.sub.3; PA1 R.sup.2 is butyl, pentyl or hexyl; PA1 z is 1 to 3; PA1 r is 2 or 3; and PA1 M is a metal ion. PA1 y is 3 or 4; PA1 R is (CH.sub.2).sub.z P(.dbd.O)OR.sup.1 OR.sup.2 ; PA1 R.sup.1 is H or CH.sub.3; PA1 R.sup.2 is butyl, pentyl or hexyl; PA1 z is 1 to 3; PA1 r is 3; and PA1 M is gadolinium.
Because of the advantages of NMR imaging (good resolution and avoidance of ionizing radiation), an NMR contrast agent capable of greater localization would be clinically important. Such an agent would offer significant advantages over contrast agents of the prior art.
3. NMR Contrast Agents
The quality of the images obtained from an NMR scan is based on two properties: the proton densities of the various tissues and differences in proton relaxation rates. The proton density of tissues cannot be readily altered. Proton relaxation rates can be adjusted by adding a paramagnetic relaxation agent, more commonly known as a "contrast agent." Contrast agents enhance the contrast in NMR images between magnetically similar but histologically dissimilar tissues.
Gadolinium, which has strong paramagnetic properties because of its seven unpaired electrons, has been tested as a contrast agent. It has a large magnetic moment which efficiently relaxes magnetic nuclei and increases tissue contrast in the region of the gadolinium.
One drawback of gadolinium as a contrast agent is its toxicity to animals, although a possible remedy for this problem is incorporation of gadolinium in a compound that would pass through the body and be excreted without releasing toxic gadolinium ions. Unfortunately, the rare earth elements (including gadolinium) do not form stable covalent bonds with organic molecules, so such molecules can decompose in vivo and release the toxic ions.
Thus, there is a need for effective contrast agents which avoid the toxicity problems inherent in using gadolinium or another metal ion. Further, it is desirable that a contrast agent control or influence the distribution of chelated ions in the body.
A even more desirable approach to the site-specific delivery of metal ions would be through use of stable chelates having inherent affinity for various tissue types. Inherent tissue affinity built into the organic chelating agent through modifications in both ionic charge and degree of lipophilic character would offer substantial advantages over currently available agents.